Use of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine to treat motion sickness

ABSTRACT

The present invention relates to the use of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine for the treatment or prevention of motion sickness. There is also provided pharmaceutical compositions and products comprising a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine.

This application is a 371 of PCT/GB96/01628, filed Jul. 8, 1996.

This invention relates to the treatment or prevention of motion sickness by the administration of a combination of a tachykinin antagonist, in particular an NK-1 receptor antagonist, and a muscarinic antagonist and/or a histamine antagonist.

Motion sickness can be produced in a number of situations which are reflected in the variety of names given to this condition, including: sea sickness, car sickness, air sickness, swing sickness and space sickness. It will be appreciated however that a subject may develop symptoms of motion sickness without being in motion. For instance, members of an audience watching a cinema film taken from a moving vehicle, such as a fairground ride, may experience symptoms of motion sickness while they themselves remain stationary.

One widely discussed explanation of the cause of motion sickness is the sensory conflict theory. The body perceives its orientation in space and changes thereof through visual input and the vestibular system located in the inner ear: angular acceleration being detected through the semi-circular canals and linear acceleration through otoliths. Other parts of the body may also add confirmatory evidence of motion, for example, cutaneous sensors, muscle spindles and tendon organs. The body will in general assume that the external visual scene as a whole remains stable in space and that gravity does not change in intensity or direction. The sensory conflict theory proposes that motion sickness occurs where infomation about motion obtained through one sensory modality is unsupported, or even contradicted, by the motion information obtained through another (for review, see C. M. Oman, Can. J. Piysiol. Pharmacol., (1990) 68, 294-303).

In a development of this theory, Treisman has proposed an explanation as to why nausea and vomiting should occur in response to sensory conflict (Science, (1977)197, 493-495). It is suggested that conflicting sensory inputs are interpretated centrally as neurophysiological dysfunction caused by poisoning, this being supported by the observation that the brain stem mechanism of orientation and motion also function to detect and respond to certain poisons (for review see K. E. Money, Mechanisms and Control of Emesis, A. L. Bianchi et al (Eds.) Colloques INSERM, John Libbey Eurotext, (1992) 223, 177-184).

Certain drugs have been used both in the prophylaxis and in the treatment of motion-induced emesis, though side-effects may limit their usefulness (see J. R. Rollin Stott, Mechanisms and Control of Emesis, A. L. Bianchi et al (Eds.) Colloques INSERM, John Libbey Eurotext, (1992) 223, 203-212). It has been shown, however, that many drugs which are used to treat nausea and vomiting from other causes (for example, chemotherapy-induced emesis) are ineffective in motion sickness. For instance, the 5-HT₃ antagonist ondansetron (GR 38032F) which possesses potent antiemetic properties in vomiting induced by cancer chemotherapeutic drugs has been shown to have no effect in man on motion sickness induced by cross-coupled stimulation (J. R. R. Stott et al., Br. J. Clin. Pharmac., (1989) 27, 147-157).

The most widely used agents use in the management of motion sickness are muscarinic antagonists and antihistamines (histamine H₁ -receptor antagonists). In general, it is preferable to administer these drugs prophylactically since they are much less effective once severe nausea and vomiting has developed.

The most commonly used muscarinic antagonists include scopolomine (l-hyoscine) and related belladona alkaloids. Antihistamines which have been shown to be effective in the prevention of motion sickness include promethazine, cinnarizine, dimenhydrinate, cyclizine and meclizine.

Scopolamine has proved to be one of the most effective drugs for short duration exposures to provocative motion, however, doses in excess of 0.6 mg are very liable to lead to side-effects, typically light headedness, drowsiness and dry mouth. Furthermore, scopolamine is not recommended for children in whom the therapeutic margin is probably narrower and who are therefore more at risk of serious toxic central effects of restlessness, hallucinations and psychosis. For similar reasons, scopolamine is not well tolerated in the elderly. It has also been suggested that scopolamine impairs short-term memory. Whilst a certain degree of sedation might, in some circumstances, be desirable, it severely limits the use of the drug where, for example, the subject is operating machinery or is in control of a vehicle. Antihistamines should also be taken with caution since they too may cause sedation.

There is therefore a need to develop methods which enable the clinician to use lower (non-sedating) doses of muscarinic antagonist and/or antihistamine, thereby reducing the likelihood of sedative and other side-effects, whilst retaining an efficacious activity against the effects of motion sickness.

Emesis may be effectively blocked by the administration of a potent, non-peptide NK-1 receptor antagonist (see, for example, Bountra et al., Eur. J. Pharmacol., (1993) 249, R3-R4; Tattersall et al., Eur. J. Pharmacol., (1993) 250, R5-R6; and Watson et al., Br. J. Pharmacol., (1995) 115, 84-94). Treatment with a muscarinic antagonist and/or an antihistamine together with an NK-1 receptor antagonist relieves the effects of motion sickness, enabling lower (non-sedating) doses of the muscarinic antagonist and/or antihistamine to be used.

The present invention accordingly provides the use of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine for the manufacture of a medicament for the treatment or prevention of motion sickness.

The present invention also provides a method for the treatment or prevention of motion sickness, which method comprises administration to a patient in need of such treatment an amount of a tachykinin antagonist and an amount of a muscarinic antagonist and/or an antihistamine such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine, together with at least one pharmaceutically acceptable carrier or excipient.

It will be appreciated that the tachykinin antagonist and muscarinic antagonist and/or antihistamine may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of motion sickness. Such combined preparations may be, for example, in the form of a twin pack.

In a further or alternative aspect of the present invention, there is therefore provided a product comprising a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of motion sickness.

The compositions of the present invention are useful for the treatment of motion sickness caused by any provocative stimulus, including sea sickness, car sickness, air sickness, space sickness, swing sickness, camel sickness, simulator sickness and cinerama sickness.

The compositions of the present invention may also be of use in the treatment of vertigo and nausea such as that associated with Meniere's disease and middle-ear surgery.

The compositions of the present invention are especially useful for the treatment of or prevention of motion sickness where the use of a muscarinic antagonist and/or an antihistamine is generally prescribed.

By the use of a combination of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine in accordance with the present invention, it is now possible to treat or prevent motion sickness with a sub-maximal dose of a muscarinic antagonist and/or an antihistamine thereby reducing the likelihood of side-effects associated with the use of such drugs (e.g. drowsiness, dry mouth, and other anticholinergic reactions).

A particularly preferred use for a composition of the present invention is in the treatment or prevention of car sickness, sea sickness, air sickness and space sickness.

The tachykinin antagonists of use in the present invention may be any tachykinin antagonist known from the art. Preferably, the tachykinin antagonist is an NK-1 or NK-2 receptor antagonist, especially an NK-1 receptor antagonist.

NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 15 0 610 793, 0 686 629, and 0 714 891; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, 93101165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 20 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94105625, 94/07843, 94110165, 94/10167, 94110168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 95/02595, 95106645, 95/07886, 95/07908, 95/08549, 95/14017, 95/15311, 95/17382, 95/18129, and 95/30687; and in British Patent Specification Nos. 2 266 529, 2 268 931,2 269 170, 2 269 590 and 2 271 774.

NK-2 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 347 802, 0 428 434, 0 474 561, 0 512 901 and 0 515 240; and in International Patent Specification Nos. 92119254 and 93/14084.

One class of tachykinin antagonists of use in the present invention is that described in European Patent Specification No. 0 577 394, i.e. compounds of formula (I): ##STR1## or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of:

(1) hydrogen;

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

(i) hydrogen,

(ii) C₁₋₆ alkyl,

(iii) hydroxy-C₁₋₆ alkyl, and

(iv) phenyl,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above,

(m) --CO₂ R⁹, wherein R⁹ is as defined above,

(n) heterocycle, wherein the heterocycle is selected from the group consisting of:

(A) benzimidazolyl,

(B) benzofuranyl,

(C) benzthiophenyl,

(D) benzoxazolyl,

(E) furanyl,

(F) imidazolyl,

(G) indolyl,

(H) isoxazolyl,

(I) isothiazolyl,

(J) oxadiazolyl,

(K) oxazolyl,

(L) pyrazinyl,

(M) pyrazolyl,

(N) pyridyl,

(O) pyrimidyl,

(P) pyrrolyl,

(Q) quinolyl,

(R) tetrazolyl,

(S) thiadiazolyl,

(T) thiazolyl,

(U) thienyl,

(V) triazolyl,

(W) azetidinyl,

(X) 1,4-dioxanyl,

(Y) hexahydroazepinyl,

(Z) oxanyl,

(AA) piperazinyl,

(AB) piperidinyl,

(AC) pyrrolidinyl,

(AD) tetrahydrofuranyl, and

(AE) tetrahydrothienyl,

and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl, unsubstituted or substituted with halo, --CF₃, --OCH₃, or phenyl,

(ii) C₁₋₆ alkoxy,

(iii) oxo,

(iv) hydroxy,

(v) thioxo,

(vi) --SR⁹, wherein R⁹ is as defined above,

(vii) halo,

(viii) cyano,

(ix) phenyl,

(x) trifluoromethyl,

(xi) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m is 0, 1 or 2, and R⁹ and R¹⁰ are as defined above,

(xii) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiv) --CO₂ R⁹, wherein R⁹ is as defined above, and

(xv) --(CH₂)_(m) --OR⁹, wherein m and R⁹ are as defined above:

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹, wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above,

(k) heterocycle, wherein the heterocycle is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹, are as defined above,

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above,

(o) --CO₂ R⁹, wherein R¹ is as defined above;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen;

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹, wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above,

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

and the groups R¹ and R² may be joined together to form a heterocyclic ring selected from the group consisting of:

(a) pyrrolidinyl,

(b) piperidinyl,

(c) pyrrolyl,

(d) pyridinyl,

(e) imidazolyl,

(f) oxazolyl, and

(g) thiazolyl,

and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(v) halo, and

(vi) trifluoromethyl;

and the groups R² and R³ may be joined together to form a carbocyclic ring selected from the group consisting of:

(a) cyclopentyl,

(b) cydohexyl,

(c) phenyl,

and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:

(i) C₁₋₆ alkyl,

(ii) C₁₋₆ alkoxy,

(iii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(iv) halo, and

(v) trifluoromethyl; and the groups R² and R³ may be joined

together to form a heterocyclic ring selected from the group consisting of:

(a) pyrrolidinyl,

(b) piperidinyl,

(c) pyrrolyl,

(d) pyridinyl,

(e) imidazolyl,

(f) furanyl,

(g) oxazolyl,

(h) thienyl, and

(i) thiazolyl,

and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(v) halo, and

(vi) trifluoromethyl;

X is selected from the group consisting of:

(1) --O--,

(2) --S--,

(3) --SO--, and

(4) --SO₂ --;

R⁴ is selected from the group consisting of: ##STR2## (2) --Y--C₁₋₈ alkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above,

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) --Y--C₂₋₆ alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹, wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above,

(4) --O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R⁶, R⁷ and R⁸ ;

R⁵ is selected from the group consisting of:

(1) phenyl, unsubstituted or substituted with one or more of R¹¹, R¹² and R¹³ ;

(2) C₁₋₈ alkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CO R⁹, wherein R⁹ is as defined above,

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹, wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) heterocycle, wherein the heterocycle is as defined above;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen;

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above;

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

(6) halo,

(7) --CN,

(8) --CF₃,

(9) --NO₂,

(10) --SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅ alkyl,

(11) --SOR¹⁴, wherein R¹⁴ is as defined above,

(12) --SO₂ R¹⁴, wherein R¹⁴ is as defined above,

(13) NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(14) CONR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(15) NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(16) NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(17) hydroxy,

(18) C₁₋₆ alkoxy,

(19) COR⁹, wherein R⁹ is as defined above,

(20) CO₂ R⁹, wherein R⁹ is as defined above,

R¹¹, R¹² and R¹³ are independently selected from the definitions of R⁶, R⁷ and R⁸, or --OX;

Y is selected from the group consisting of:

(1) a single bond,

(2) --O--,

(3) --S--,

(4) --CO--,

(5) --CH₂ --,

(6) --CHR¹⁵ --, and

(7) --CR¹⁵ R¹⁶ --, wherein R¹⁵ and R¹⁶ are independently selected from the group consisting of:

(a) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(i) hydroxy,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) phenyl-C₁₋₃ alkoxy,

(v) phenyl,

(vi) --CN,

(vii) halo,

(viii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(ix) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xii) --COR⁹, wherein R⁹ is as defined above, and

(xiii) --CO₂ R⁹, wherein R⁹ is as defined above;

(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) C₁₋₆ alkyl,

(iv) C₂₋₅ alkenyl,

(v) halo,

(vi) --CN,

(vii) --NO₂,

(viii) --CF₃,

(ix) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xii) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiv) --COR⁹, wherein R⁹ is as defined above, and

(xv) --CO₂ R⁹, wherein R⁹ is as defined above;

Z is selected from:

(1) hydrogen,

(2) C₁₋₄ alkyl, and

(3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR¹⁵ --, then Z and R¹⁵ may be joined together to form a double bond.

A particularly preferred compound of formula (I) is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)pheny)lethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention are compounds of formula (II): ##STR3## or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) and R^(b) each independently represent hydrogen or C₁₋₄ alkyl;

R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy or CF₃ ;

R³ is hydrogen, halogen or CF₃ ;

R⁴ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) and R^(b) each independently represent hydrogen or C₁₋₄ alkyl;

R⁵ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy or CF₃ ;

R⁶ is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by ═O, ═S or a C₁₋₄ alkyl group, and optionally substituted by a group of the formula ZNR⁷ R⁸ where

Z is C₁₋₆ alkylene or C₃₋₆ cycloalkylene;

R⁷ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxyl;

R⁸ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by one or two substituents selected from C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;

or R⁷, R⁸ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂ or a second nitrogen atom which will be part of a NH or NR^(c) moiety where R^(c) is C₁₋₄ alkyl optionally substituted by hydroxy or C₁₋₄ alkoxy;

or R⁷, R⁸ and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;

or Z, R⁷ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;

R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄ alkyl, or R^(9a) and R^(9b) are joined so, together with the carbon atoms to which they are attached, there is formed a C₅₋₇ ring;

X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and

Y is a C₁₋₄ alkyl group optionally substituted by a hydroxyl group;

with the proviso that if Y is C₁₋₄ alkyl, R⁶ is susbstituted at least by a group of formula ZNR⁷ R⁸ as defined above.

A particularly preferred compound of formula (II) is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention are those compounds of formula (III): ##STR4## or a pharmaceutically acceptable salt thereof, wherein: R² and R³ are independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

(I) hydrogen,

(ii) C₁₋₆ alkyl,

(iii) hydroxy-C₁₋₆ alkyl, and

(iv) phenyl,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --NR⁹ CO₂ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ RID, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above,

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

and the groups R² and R³ may be joined together to form a carbocyclic ring selected from the group consisting of:

(a) cyclopentyl,

(b) cyclohexyl,

(c) phenyl,

and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:

(i) C₁₋₆ alkyl,

(ii) C₁₋₆ alkoxy,

(iii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(iv) halo, and

(v) trifluoromethyl;

and the groups R² and R³ may be joined together to form a heterocyclic ring selected from the group consisting of:

(a) pyrrolidinyl,

(b) piperidinyl,

(c) pyrrolyl,

(d) pyridinyl,

(e) imidazolyl,

(f) furanyl,

(g) oxazolyl,

(h) thienyl, and

(i) thiazolyl,

and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(v) halo, and

(vi) trifluoromethyl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen;

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above,

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

(6) halo,

(7) --CN,

(8) --CF₃,

(9) --NO₂,

(10) --SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅ alkyl,

(11) --SOR¹⁴, wherein R¹⁴ is as defined above,

(12) --SO₂ R¹⁴, wherein R¹⁴ is as defined above,

(13) NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(14) CONR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(15) NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(16) NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(17) hydroxy,

(18) C₁₋₆ alkoxy,

(19) COR⁹, wherein R⁹ is as defined above,

(20) CO₂ R⁹, wherein R⁹ is as defined above,

(21) 2-pyridyl,

(22) 3-pyridyl,

(23) 4-pyridyl,

(24) 5-tetrazolyl,

(25) 2-oxazolyl, and

(26) 2-thiazolyl;

R¹¹, R¹² and R¹³ are independently selected from the definitions of R⁶, R⁷ and R⁸, or --OX;

A is selected from the group consisting of:

(1) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo, wherein halo is fluoro, chloro, bromo or iodo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(2) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R¹ is as defined above, and

(j) --CO₂ R⁹, wherein R⁹ is as defined above; and

(3) C₂₋₆ alkynyl;

B is a heterocycle, wherein the heterocycle is selected from the group consisting of: ##STR5## and wherein the heterocycle may be substituted in addition to --X with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl, unsubstituted or substituted with halo, --CF₃, --OCH₃, or phenyl,

(ii) C₁₋₆ alkoxy,

(iii) oxo,

(iv) hydroxy,

(v) thioxo,

(vi) --SR⁹, wherein R⁹ is as defined above,

(vii) halo,

(viii) cyano,

(ix) phenyl,

(x) trifluoromethyl,

(xi) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m is 0, 1 or 2, and R⁹ and R¹⁰ are as defined above,

(xii) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiv) --CO₂ R⁹, wherein R⁹ is as defined above, and

(xv) --(CH₂)_(m) --OR⁹, wherein m and R⁹ are as defined above;

p is 0 or 1;

X is selected from:

(a) --PO(OH)O-- . M⁺, wherein M⁺ is a pharmaceutically acceptable monovalent counterion,

(b) --PO(O--)² . 2M⁺,

(c) --PO(O--)² . D²⁺, wherein D²⁺ is a pharmaceutically acceptable divalent counterion,

(d) --CH(R⁴)--PO(OH)O . M⁺, wherein R¹ is hydrogen or C₁₋₃ alkyl,

(e) --CH(R⁴)--PO(O--)₂ . 2M⁺,

(f) --CH(R⁴)--PO(O--)² . D²⁺,

(g) --SO₃ -- . M⁺,

(h) --CH(R⁴)--SO₃ -- . M⁺,

(i) --CO--CH₂ CH₂ --CO₂ -- . M⁺,

(j) --CH(CH₃)--O--CO--R⁵, wherein R⁵ is selected from the group consisting of: ##STR6## (k) hydrogen, with the proviso that if p is 0 and none of R¹¹, R¹² or R¹³ are --OX, then X is other than hydrogen;

Y is selected from the group consisting of:

(1) a single bond,

(2) --O--,

(3) --S--,

(4) --CO--,

(5) --CH₂ --,

(6) --CHR¹⁵ --, and

(7) --CR¹⁵ R¹⁶ --, wherein R¹⁵ and RIG are independently selected from the group consisting of:

(a) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(i) hydroxy,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) phenyl-C₁₋₃ alkoxy,

(v) phenyl,

(vi) --CN,

(vii) halo,

(viii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(ix) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xii) --COR⁹, wherein R⁹ is as defined above, and

(xiii) --CO₂ R⁹, wherein R⁹ is as defined above;

(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) C₁₋₆ alkyl,

(iv) C₂₋₅ alkenyl,

(v) halo,

(vi) --CN,

(vii) --NO₂,

(viii) --CF₃,

(ix) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --NR⁹ CO₂ Ro, wherein R⁹ and R¹⁰ are as defined above,

(xii) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CO₂ NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(xiv) --CO R⁹, wherein R⁹ is as defined above, and

(xv) --CO₂ R⁹, wherein R⁹ is as defined above;

Z is selected from:

(1) hydrogen,

(2) C₁₋₆ alkyl, and

(3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR¹⁵ --, then Z and R¹⁵ may be joined together to form a double bond.

A particularly preferred compound of formula (III) is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in European Patent Specification No. 0 436 334, i.e. compounds of formula (IV): ##STR7## or a pharmaceutically acceptable salt thereof, wherein Y is (CH₂)n wherein n is an integer from 1 to 4, and wherein any one of the carbon--carbon single bonds in said (CH₂)_(n) may optionally be replaced by a carbon--carbon double bond, and wherein any one of the carbon atoms of said (CH₂)_(n) may optionally be substituted with R⁴, and wherein any one of the carbon atoms of said (CH₂)_(n) may optionally be substituted with R⁷ ;

Z is (CH₂)_(m) wherein m is an integer from 0 to 6, and wherein any one of the carbon--carbon single bonds of (CH₂)_(m) may optionally be replaced by a carbon--carbon double bond or a carbon--carbon triple bond, and any one of the carbon atoms of said (CH₂)_(m) may optionally be substituted with R⁸ ;

R¹ is hydrogen or C₁₋₈ alkyl optionally substituted with hydroxy, C₁₋₄ alkoxy or fluoro;

R² is a radical selected from hydrogen, C₁₋₆ straight or branched alkyl, C₃₋₇ cycloalkyl wherein one of the CH₂ groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C₂₋₆ alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -C₂₋₆ alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, trifluoromethyl, amino, C₁₋₆ alkylamino, C₁₋₆ alkyl--O--CO, C₁₋₆ alkyl--O--CO--C₁₋₆ alkyl, C₁₋₆ alkyl--CO--O, C₁₋₆ alkyl--CO--C₁₋₆ alkyl--O--, C₁₋₆ alkyl--CO, C₁₋₆ alkyl--CO--C₁₋₆ alkyl-, di-C₁₋₆ alkylamino, --CONH--C₁₋₆ alkyl, C₁₋₆ alkyl--CO--NH--C₁₋₆ alkyl, --NHCOH and --NHCO--C₁₋₆ alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;

R⁵ is hydrogen, phenyl or C₁₋₆ alkyl;

or R² and R⁵ together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH₂ groups in said ring may optionally be replaced by oxygen, NH or sulfur;

R³ is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH₂) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;

wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C₃₋₇ cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, trifluoromethyl, amino, C₁₋₆ alkylamino, --CO--NH--C₁₋₆ alkyl, C₁₋₆ alkyl--CO--NH--C₁₋₆ alkyl, --NHCOH and --NHCO--C₁₋₆ alkyl;

R⁴ and R⁷ are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl--O--CO, C₁₋₆ alkyl--O--CO--C₁₋₆ alkyl, C₁₋₆ alkyl--CO--O, C₁₋₆ alkyl--CO--Cialkyl--O--, C₁₋₆ alkyl--CO--, C₁₋₆ alkyl--CO--C₁₋₆ alkyl, and the radicals set forth in the definition of R² ;

R⁶ is --NHCOR⁹, --NHCH₂ R⁹, SO₂ R⁸ or one of the radicals set forth in any of the definitions of R², R⁴ and R⁷ ;

R⁸ is oximino (═NOH) or one of the radicals set forth in any of the definitions of R², R⁴ and R⁷ ;

R⁹ is C₁₋₆ alkyl, hydrogen, phenyl or phenylC₁₋₆ alkyl;

with the proviso that (a) when m is 0, R⁸ is absent, (b) when R⁴, R⁶, R⁷ or R⁸ is as defined in R², it cannot form together with the carbon to which it is attached, a ring with R⁵, and (c) when R⁴ and R⁷ are attached to the same carbon atom, then either each of R⁴ and R⁷ is independently selected from hydrogen, fluoro and C₁₋₆ alkyl, or R⁴ and R⁷, together with the carbon to which they are attached, for a C₃₋₆ saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.

A particularly preferred compound of formula (IV) is (2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (V): ##STR8## or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;

R¹ is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;

R² is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;

R³ is optionally 2-substituted phenyl;

R⁴ is OH or fluorine when R⁵ is H;

or R⁴ and R⁵ are OH;

or R⁴ and R⁵ together form a bond.

A particularly preferred compound of formula (V) is (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in European Patent Specification No. 0 591 040, i.e. compounds of formula (VI): ##STR9## wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;

T represents a bond, a hydroxymethylene group, a C₁₋₄ alkoxymethylene group or a C₁₋₅ alkylene group;

Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C₁₋₄ alkoxy, C₁₋₄ alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;

R represents hydrogen, C₁₋₄ alkyl, ω-C₁₋₄ alkoxyC₁₋₄ alkyl, or 1-C₂₋₄ alkanoyloxyC₂₋₄ alkyl;

Q represents hydrogen;

or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;

Am⁺ represents the radical ##STR10## in which X₁, X₂ and X₃, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and

A represents a pharmaceutically acceptable anion.

A particularly preferred compound of formula (VI) is (+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.

Another class of tachykinin antagonists of use in the present invention is that described in European Patent Specification No. 0 532 456, i.e. compounds of formula (VI): ##STR11## or a pharmaceutically acceptable salt thereof, wherein R¹ represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an α-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;

R² represents cycloalkyl or an optionally substituted aryl or heteroaryl group;

R³ represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;

R⁴ represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;

X₁ represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;

X₂ represents alkylene, carbonyl or a bond; and

X₃ represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the α-position) hydroxy.

A particularly preferred compound of formula (VII) is (2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in European Patent Specification No. 0 443 132, i.e. compounds of formula (VIII) ##STR12## wherein R¹ is aryl, or a group of the formula: ##STR13## or a pharmaceutically acceptable salt thereof, wherein X is CH or N; and

Z is O or N--R⁵, in which R⁵ is hydrogen or lower alkyl;

R² is hydroxy or lower alkoxy;

R³ is hydrogen or optionally substituted lower alkyl;

R⁴ is optionally substituted ar(lower)alkyl;

A is carbonyl or sulfonyl; and

Y is a bond or lower alkenylene.

A particularly preferred compound of formula (VIII) is the compound of formula (VIIIa) ##STR14## or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO 95/08549, i.e. compounds of formula (IX): ##STR15## wherein R¹ is a C₁₋₄ alkoxy group; R² is ##STR16## R³ is a hydrogen or halogen atom; R⁴ and R⁵ may each independently represent a hydrogen or halogen atom, or a C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl group;

R⁶ is a hydrogen atom, a C₁₋₄ alkyl, (CH₂)_(m) cyclopropyl, --S(O)_(n) C₁₋₄ alkyl, phenyl, NR⁷ R⁸, CH₂ C(O)CF₃ or trifluoromethyl group;

R⁷ and R⁸ may each independently represent a hydrogen atom, or a C₁₋₄ alkyl or acyl group;

x represents zero or 1;

n represents zero, 1 or 2;

m represents zero or 1;

and pharmaceutically acceptable salts and solvates thereof.

Particularly preferred compounds of formula (IX) are (2S,3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine, (2S,3S)-2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl-(2-phenyl-piperidin-3-yl)-amine, or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO 95/14017, i.e. compounds of formula (X) ##STR17## or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3;

n is zero or 1;

o is zero, 1 or 2;

p is zero or 1;

R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;

which R groups may be substituted with one or two halo, C₁₋₃ alkoxy, trifluoromethyl. C₁₋₄ alkyl, phenyl-C₁₋₃ alkoxy, or C₁₋₄ alkanoyl groups;

R¹ is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C₁₋₄ alkyl)-, phenyl-(C₁₋₄ alkoxy)-, quinolinyl-(C₁₋₄ alkyl)-, isoquinolinyl-(C₁₋₄ alkyl)-, reduced quniolinyl-(C₁₋₄ alkyl)-, reduced isoquinolinyl-(C₁₋₄ alkyl)-, benzoyl-(C₁₋₃ alkyl)-, C₁₋₄ alkyl, or --NH--CH₂ -R⁵ ;

any one of which R¹ groups may be substituted with halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, or C₂₋₄ alkanoylamino;

or any one of which R¹ groups may be substituted with phenyl, piperazinyl, C₃₋₈ cycloalkyl, benzyl, C₁₋₄ alkyl, piperidinyl, pyridinyl, pyrimidinyl, C₂₋₆ alknoylamio, pyrrolidinyl, C₂₋₆ alkanoyl, or C₁₋₄ alkoxycarbonyl;

any one of which groups may be substituted with halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, or C₂₋₄ alkanoylamino;

or R¹ is amino, a leaving group, hydrogen, C₁₋₄ alkylamino, or di(C₁₋₄ alkyl)amino;

R⁵ is pyridyl, anilino-(C₁₋₃ alkyl)-, or anilinocarbonyl;

R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, carboxy-(C₁₋₃ alkyl)-, C₁₋₃ alkoxycarbonyl-(C₁₋₃ alkyl)-, or --CO--R⁶ ;

R⁶ is hydrogen, C₁₋₄ alkyl, C₁₋₃ haloalkyl, phenyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, or --(CH₂)_(q) --R⁷ ;

q is zero to 3;

R⁷ is carboxy, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylcarbonyloxy, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₆ alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C₁₋₄ alkyl)-, quinolinyl-(C₁₋₄ alkyl)-, isoquinolinyl-(C₁₋₄ alkyl)-, reduced quinolinyl-(C₁₋₄ alkyl)-, reduced isoquinolinyl-(C₁₋₄ alkyl)-, benzoyl-C₁₋₃ alkyl;

any one of which aryl or heterocyclic R⁷ groups may be substituted with halo, trifluoromethyl, C₁₋₄ alkoxy, C₁₋₄ alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, or C₂₋₄ alkanoylamino;

or any one of which R⁷ groups may be substituted with phenyl, piperazinyl, C₃₋₈ Cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C₂₋₄ alkanoyl, or C₁₋₄ alkoxycarbonyl;

any of which groups may be substituted with halo, trifluoromethyl, amino, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, or C₂₋₄ alkanoylamino;

R⁸ is hydrogen or C₁₋₆ alkyl;

R³ is phenyl, phenyl-(C₁₋₆ alkyl)-, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, C₁₋₈ alkyl, naphthyl, C₂₋₈ alkenyl, or hydrogen;

any one or which groups except hydrogen may be substituted with one or two halo, C₁₋₃ alkoxy, C₁₋₃ alkylthio, nitro, trifluoromethyl, or C₁₋₃ alkyl groups; and

R⁴ is hydrogen or C₁₋₃ alkyl;

with the proviso that if R¹ is hydrogen or halo, R³ is phenyl, phenyl-(C₁₋₆ alkyl)-, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, or naphthyl.

A particularly preferred compound of formula (X) is [N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylamino]propane; or a pharmaceutically acceptable salt thereof.

Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.

Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.

Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.

A particular aryl-C₁₋₆ alkyl, e.g. phenyl-C₁₋₆ alkyl, group is benzyl.

Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.

Suitable pharmaceutically acceptable salts of the tachykinin antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.

Suitable muscarinic antagonists of use in the present invention include scopolamine (l-hyoscine); or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts of the muscarinic antagonists of use in the present invention include those salts described above in relation to the salts of tachykinin antagonists.

Preferred salts of l-hyoscine of use in the present invention include the hydrobromide salt.

Suitable antihistamines of use in the present invention include buclizine, chiorcyclizine, cinnarizine, cyclizine, dimenhydrinate, diphenhydramine, flunarizine, meclozine, pheniramnine, promethazine and propiomazine; or a pharmaceutically acceptable salt thereof.

A further sub-class of compound with antihistamine and pronounced anti-muscarinic activity are phenothiazines and related compounds. Promethazine is the archetypal phenothiazine. Other examples include chlorpromazine, methotimeprazine, perphenazine, prochlorperazine and trifluoperazine; and pharmaceutically acceptable salts thereof.

Suitable pharmaceutically acceptable salts of the antihistamines of use in the present invention include those salts described above in relation to the tachykinin antagonists.

Preferred salts of antihistamines of use in the present invention include buclizine hydrochloride, chlorcyclizine hydrochloride, cyczine hydrochloride, cylizine lactate, cyclizine tartrate, diphenhydramine citrate, diphenhydramine di(acefyllinate) [bis(theophyllin-7-ylacetate)], diphenhydramine hydrochloride, flunarizine hydrochloride, meclozine hydrochloride, pheniramine aminosalicylate, pheniramine maleate, promethazine hydrochloride, promethazine theoclate, propiomazine hydrochloride and propiomazine maleate.

Preferred salts of the phenothiazines listed above include, in addition to promethazine hydrochloride and promethazine theoclate, chlorpromethazine hydrochloride, prochlorperazine maleate and prochlorperazine mesylate.

Particularly preferred antihistamines of use in the present invention include cinnarizine, cyclizine, dimenhydrinate, meclizine and promethazine; or a pharmaceutically acceptable salt thereof.

As stated above, the tachykinin antagonist and muscarinic antagonist and/or antihistamine may be formulated in a single pharmaceutical composition or alternatively in individual pharmaceutical compositions for simultaneous, separate or sequential use in accordance with the present invention.

Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal patches or by buccal cavity absorption wafers.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include those comprising a tachykinin antagonist, as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).

Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared by mixing a tachykinin antagonist with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.

The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a tachykinin antagonist and a muscarinic antagonist and/or antihistamine, which process comprises bringing a tachykinin antagonist and a muscarinic antagonist and/or antihistamine, into association with a pharmaceutically acceptable carrier or excipient.

When administered in combination, either as a single or as separate pharmaceutical composition(s), the tachykinin antagonist and the muscarinic antagonist and/or antihistamine are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the tachykinin antagonist to the muscarinic antagonist and/or antihistamine will suitably be approximately 1 to 1. Preferably this ratio will be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.

A suitable dosage level for the tachykinin antagonist is. about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day.

The muscarinic antagonist may be administered at a dosage level up to conventional dosage levels for such drugs, but preferably at a reduced level in accordance with the present invention. Suitable dosage levels will depend upon the anti-emetic effect of the chosen muscarinic antagonist, but typically suitable levels will be about 0.01 to 10 mg per day, preferably 0.05 to 5 mg per day, and especially 0.05 to 1 mg per day. The compound may be administered on a regimen of up to 4 times per day, preferably 1 to 3 times per day.

The antihistamine may be administered at a dosage level up to conventional dosage levels for such drugs, but preferably at a reduced level in accordance with the present invention. Suitable dosage levels will depend upon the anti-emetic effect of the chosen antihistamine, but typically suitable levels will be about 0.01 to 200 mg per day, preferably 0.5 to 100 mg per day, and especially 0.5 to 50 mg per day. The compound may be administered on a regimen of 4 times per day, preferably 1 to 3 times per day.

When administered in combination, either as a single or as separate pharmaceutical composition(s), the tachykinin antagonist and the muscarinic antagonist and/or antihistamine will be preferably administered between 30 minutes and 2 hours before the subject is exposed to the provocative motion.

It will be appreciated that the amount of a tachykinin antagonist and muscarinic antagonist and/or antihistamine required for use in the treatment or prevention of motion sickness will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.

The compounds of formulae (I), (IV), (V), (VI), (VII), (VIII) and (IX) may be prepared by the methods described in EP-A-0 577 394, EP-A-0 436 334, WO-A-93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, and WO-A-95/08549, respectively.

The compounds of formula (II) may be prepared by a variety of methods, thus, according to a general process, the compounds of formula (II) may be prepared from compounds of formula (A) ##STR18## wherein R¹, R², R³, R⁴, R⁵, R^(9a), R^(9b) and Y are as defined in relation to formula (II) by reaction with a compound of formula (B):

    X.sub.1 --X--R.sup.6n                                      (B)

where X is as defined in relation to formula (II), R^(6a) is a group of the formula R⁶ as defined in relation to formula (II) or a precursor therefor and X¹ is a leaving group such as bromine or chlorine; and, if R^(6a) is a precursor group, converting it to a group R⁶ (in which process any reactive group may be protected and thereafter deprotected if desired).

This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.

According to another process, compounds of formula (II) wherein R⁶ represents 1,2,3-triazol-4-yl substituted by CH₂ NR⁷ R⁸, and X is --CH₂ --, may be prepared by reaction of a compound of formula (C): ##STR19## with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at a temperature of between 40° C. and 100° C., followed by reduction of the carbonyl group adjacent to --NR⁷ R⁸ using a suitable reducing agent such as lithium aluminium hydride at at a temperature between -10° C. and room temperature, conveniently at room temperature.

Alternatively, according to another process, compounds of formula (II) wherein R⁶ represents 1,2,3-triazol-4-yl substituted by CH₂ NR⁷ R⁸, and X is --CH₂ --, may be prepared by reaction of a compound of formula (D) ##STR20## with an amine of formula NHR⁷ R⁸, in a suitable solvent such as an ether, for example, dioxan, at elevated temperature, for example, between 50° C. and 100° C., in a sealed tube, or the like. This reaction is based upon that described in Chemische Berichte (1989) 122, p. 1963.

According to another process, compounds of formula (II) wherein R⁶ represents substituted or unsubstituted 1,3,5-triazine may be prepared by reaction of intermediates of formula (E): ##STR21## with substituted or unsubstituted 1,3,5-triazine.

The reaction is conveniently effected in a suitable organic solvent, such as acetonitrile, at elevated temperature, such as 80-90° C., preferably about 82° C.

According to a further process, compounds of formula (II) wherein R⁶ represents substituted or unsubstituted 1,2,4-triazine may be prepared by reaction of an intermediate of formula (F) with a dicarbonyl compound of formula (G): ##STR22## wherein R³⁵ represents H or a suitable substituent such as ZNR⁷ R⁸.

The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, conveniently at ambient temperature.

According to a further process, compounds of formula (II) wherein R⁶ represents a substituted 1,2,4-triazolyl group may be prepared by reaction of an intermediate of formula (A) with a compound of formula (H) ##STR23## wherein X is as defined in relation to formula (II), Hal is a halogen atom, for example, bromine, chlorine or iodine and R¹⁸ is H, CONH₂ or OCH₃ (which is converted to an oxo substituent under the reaction conditions) in the presence of a base, followed where necessary by conversion to a compound of formula (II), for example, by reduction of the CONH₂ group to CH₂ NH₂.

Suitable bases of use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is conveniently effected in an anhydrous organic solvent such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140° C.

A suitable reducing agent for the group CONH₂ is lithium aluminium hydride, used at between -10° C. and room temperature. According to another process, compounds of formula (II) wherein R⁶ represents thioxotriazolyl may be prepared from intermediates of formula (J): ##STR24## by reaction with a compound of formula HNCS, in the presence of a base.

Suitable bases of use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is conveniently effected in a suitable orgainc solvent, such as alcohol, e.g. butanol.

Compounds of formula (II) may also be prepared from other compounds of formula (II) using suitable interconversion procedures. For example, compounds of formula (II) wherein X represents C₁₋₄ alkyl may be prepared from compounds of formula (II) wherein X represents C₁₋₄ alkyl substituted by oxo by reduction, for example, using borane or lithium aluminium hydride. Suitable interconversion procedures will be readily apparent to those skilled in the art.

Intermediates of formula (C) may be prepared from intermediates of formula (A) by reaction with an acetylene compound of formula HC.tbd.C--CH₂ --Hal in the presence of a base such as potassium carbonate in a suitable solvent such as dimethylformamide, conveniently at room temperature, followed by reaction of the resultant acetylene intermediate with an amide of formula Hal--CO--NR⁷ R⁸ in the presence of suitable catalysts including bis(triphenylphosphine) palladium(II) chloride, copper(I) iodide and triphenylphosphine in a suitable solvent such as triethylamine, preferably at reflux.

Intermediates of formula (D) may be prepared from a compound of formula (K): ##STR25## wherein Hal is a halogen atom, for example, chlorine, bromine or iodine, especially chlorine, by reaction with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at a temperature between 40° C. and 100° C.

Compounds of formula (K) may be prepared by a dropwise addition of an intermediate of formula (A) to a dihaloacetylene of formula Hal--CH₂ --C.tbd.C--CH₂ --Hal where each Hal is independently chlorine, bromine or iodine, especially chlorine. The reaction is conveniently effected in a suitable solvent such as dimethylformamide in the presence of a base such as potassium carbonate.

Intermediates of formula (E) may be prepared from intermediates of formula (A) by reaction with a compound of formula Hal--X--C(NH)NH₂ where Hal and X are as previously defined.

Intermediates of formula (F) may be prepared from intermediates of formula (A) by reaction with a compound of formula Hal--X--C(NH)NHNH--Boc, wherein Hal and X are as previously defined and Boc stands for tert-butoxycarbonyl, followed by deprotection under acidic conditions.

Compounds of formula (G) are commercially available or may be prepared from commercially available compounds by known methods.

Compounds of formula (H) may be prepared as described in J. Med. Chem., 27, 849 (1984).

Intermediates of formula (J) may be prepared from the corresponding ester by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temperature.

For compounds wherein R⁶ is a heterocycle substituted by a ZNR⁷ R⁸ group where Z is CH₂, certain favoured compounds of formula (II) may be prepared from a corresponding compound with a hydrogen atom in place of the ZNR⁷ R⁸. Thus, for example a compound of the formula (II) wherein R⁶ is an imidazolinone group carrying a CH₂ NR⁷ R⁸ moiety may be prepared from a corresponding compound lacking the CH₂ NR⁷ R⁸ moiety by reaction with formaldehyde and an amine NHR⁷ R⁸ under conventional Mannich reaction conditions, for example in methanol with heating. If desired, a pre-formed reagent such as R⁷ R⁸ N⁺ ═CH₂ . I-- may be employed and a tertiary amine such as triethylamine used as acid acceptor.

Alternatively a compound of formula (II) wherein R⁶ is an imidazolinone group lacking a CH₂ NR⁷ R⁸ may be reacted with paraformaldehyde and an amine for example a secondary amine such as pyrrolidine or morpholine to give a compound wherein the imidazolinone ring is substituted by CH₂ NR⁷ R⁸ where R⁷, R⁸ and the nitrogen atom to which they are attached form a heteroahphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom or a second nitrogen atom which will be part of a NH or NRC moiety, where R^(c) is as defined in formula (II).

This reaction may be performed in a conventional manner, for instance, in a suitable solvent such as an alcohol, for example, methanol at an elevated temperature up to the boiling point of the solvent.

A further alternative method for the preparation of certain compounds of formula (II) involves the reaction of an intermediate of formula (A) as defined above with one of the compounds of formula (L): ##STR26## wherein each LG, which may be the same or different, is a leaving group, such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom, (e.g. bromine, chlorine or iodine), and X and Z are as defined in formula (II), followed by reaction of the resultant compound with an amine NHR⁷ R⁸ to complete the ZNR⁷ R⁸ moiety if desired.

This reaction is conveniently effected in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.

It will be appreciated that, where necessary, reactive groups may be protected, thus for example, the NH groups of an imidazolinone of formula (La) may be protected by any suitable amine protecting group such as an acetyl group.

The preferred phosphate prodrugs of the compounds of formula (II) may be prepared in a stepwise manner from a compound of formula (II) wherein Y is, for example, --CH₂ OH--.

Thus, the hydroxy compound is first treated with dibenzyloxydiethylamino-phosphine in a suitable solvent such as tetrahydrofuran, preferably in the presence of an acid catalyst such as tetrazole. The resultant compound (where Y=CH₂ OP(OCH₂ Ph)₂) is then oxidised using, for example, 4-methylmorpholine-N-oxide to give the dibenzyl-protected phosphate. Deprotection by catalytic hydrogenation or transfer hydrogenation (palladium catalyst on carbon and ammonium formate), in a suitable solvent such as methanol at reflux, yields the desired phosphate prodrug which may be converted to any desired salt form by conventional methodology.

In an alternative two-step method, the hydroxy compound of formula (I) may be reacted with a suitable reducing agent such as sodium hydride in tetrahydrofuran, and tetrabenzylpyrophosphate added to yield the dibenzyl-protected phosphate which may be deprotected as described above.

The compounds of the formula (A) may be prepared as shown in Scheme 1 in which Ar¹ represents the R¹, R², R³ substituted phenyl group; Ar² represents the R⁴, R⁵ substituted phenyl group and Ph represents phenyl: ##STR27##

The following references describe methods which may be applied by the skilled worker to the chemical synthesis set forth above once the skilled worker has read the disclosure herein.

(i) D. A. Evans et al., J. Am. Chem. Soc., (1990) 112, 4011.

(ii) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849.

(iii) R. Duschinsky et al., J. Am. Chem. Soc., (1948) 70, 657.

(iv) F. N. Tebbe et al., J. Am. Chem. Soc., (1978) 100, 3611.

(v) N. A. Petasis et al., J. Am. Chem. Soc., (1990) 112, 6532.

(vi) K. Takai et al., J. Org. Chem., (1987) 52, 4412.

The Examples disclosed herein produce predominently the preferred isomers. The unfavoured isomers are also produced as minor components. If desired they may be isolated and employed to prepare the various stereoisomers in conventional manner, for example chromatography using an appropriate chiral column. However, the skilled worker will appreciate that although the Examples have been optimized to the production of the preferred isomers, variation in solvent, reagents, chromatography etc can be readily employed to yield the other isomers.

L-Selectride is lithium tri-sec-butylborohydride.

It will be appreciated that compounds of the formula (II) wherein R⁶ contains an ═O or ═S substituent can exist in tautomeric forms. All such tautomeric forms and mixtures thereof are included within this invention. Most aptly the ═O or ═S substituent in R⁶ is the ═O substituent.

Where they are not commercially available, the intermediates of formula (B) above may be prepared by procedures which will be readily apparent to one skilled in the art.

The compounds of formula (III) may be prepared by conventional methods using methodology described above for compounds of formula (II), and those described in EP-A-0 577 394. The following schemes and description (in which the various substituents are as defined in formula (III)) also serve to illustrate suitable methods: ##STR28##

As depicted in Scheme 2, treatment of, for example, a triazolone or imidazolone-containing tachykinin antagonist with a suitable base, such as n-butyllithium, sodium hydride, potassium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisoporpylamine in THF at low temperature followed by addition of an appropriate phosphoryl transfer reagent, for example, tetrabenzyl pyrophosphate, dibenzyl phosphochloridate or dibenzyl phosphofluoridate provides an intermediate with a protected phosphoryl group. Following purifcation, for example by gravity silica gel chromatography, the dibenzyl ester may be converted into the desired product by hydrogenolysis, for example with hydrogen gas in the presence of palladium on carbon in the presence of two equivalents of a suitable salt forming agent, such as sodium bicarbonate (to prepare the disodium salt of the phosphoramidate product) or potassium bicarbonate (to prepare the dipotassium salt of the product). The product may be purified by crystallization or by normal or reverse phase chromatography.

As depicted in Scheme 3, treatment of, for example, a triazolone or imidazolone-containing tachykinin antagonist with a suitable base, such as diisopropylethylamine, 2,6-dimethylpyridine or triethylanmine and 1-chloroethyl ethyl carbonate in a compatible solvent such as toluene or dichloroethane, followed by heating the mixture at reflux for 12-24 hr, provides the corresponding N-alkylcarbonate product, which may be purified by flash chromatography.

Similarly, the same substrate may be treated with the functionalized carbonate given in Scheme 4 under similar conditions, such as refluxing in toluene in the presence of diisopropylethylamine, 2,6-dimethylpyridine or triethylamine to provide the N-Boc protected intermediate. Cleavage of the Boc group, for example with trirluoroacetic acid in methylene chloride or with hydrogen chloride in ethyl acetate provides the corresponding salt of the prodrug product.

Generation of the N-oxide prodrug of the aforementioned morpholine tachykinin antagonists may be achieved as shown in Scheme 5 simply by treatment with an oxygen-transfer agent, such as a peracid, such as 3-chloroperoxybenzoic acid of trifluoromethylperacetic acid, or with hydrogen peroxide or alkyl hydroperoxides such as t-butyl hydroperoxide in the presnce of a transition metal catalyst, or with Caro's acid (H₂ SO₅).

Compounds containing linking groups between the heterocycle and the phosphoryl group may also be prepared, for example as illustrated in Scheme 6 (see S. A. Varia et al, J. Pharm. Sci., (1984) 73, 1068-1073). Treatment of the parent compound with an aliphatic aldehyde, for example aqueous formaldehyde, provides the corresponding hydroxymethyl derivatives, which after conversion to the chloride with phosphorus trichloride, may be treated with silver dibenzyl phosphate. The resulting protected phosphates may be separated by conventional means, for example silica gel chromatography. The purified products may then be converted to the free phosphoric acids as depicted in Schemes 7 and 8, by treatment with a reducing agent such as hydrogen gas in the presence of pallidium on carbon.

The compounds of formula (III) obtained according to the reactions as explained above may be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

In addition to the above synthetic methods and the teaching in the prior art referenced above, the following non-limiting examples describe the preparation of specific tachykinin antagonists of use in the present invention:

DESCRIPTION 1

(S)-(4-Fluoronhenyl) glycine

Via Chiral Synthesis:

Step A: 3-(4-Fluoronhenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.09 g (33.0 mmol) of 4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution was cooled to -10° C. and treated with 5.60 ml (40.0 mmol) of triethylamine followed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A white precipitate formed immediately. The resulting mixture was stirred at -10° C. for 40 minutes, then cooled to -78° C.

An oven-dried, 250 ml round bottom flask, equipped with a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 ml of dry THF. The solution was stirred in a dry ice/acetone bath for 10 minutes, then 18.8 ml of 1.6M n-butyllithium solution in hexanes was slowly added. After 10 minutes, the lithiated oxazolidinone solution was added, via cannula, to the above mixture in the 3-necked flask. The cooling bath was removed from the resulting mixture and the temperature was allowed to rise to 0° C. The reaction was quenched with 100 ml of saturated aqueous ammonium chloride solution, transferred to a 1 l flask, and the ether and THF were removed in vacuo. The concentrated mixture was partitioned between 300 ml of methylene chloride and 50 ml of water and the layers were separated. The organic layer was washed with 100 ml of 2N aqueous hydrochloric acid solution, 300 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95 g of an oil that slowly solidified on standing. Recrystallisation from 10:1 hexanes/ether afforded 7.89 g (83%) of the title compound as a white solid: ¹ H NMR (400 MHz, CDCl₃) δ 2.76 (1H, dd, J=13.2, 9.2 Hz), 3.26 (dd, J=13.2, 3.2 Hz), 4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H, m).

Analysis Calcd. for C₁₈ H₁₆ FNO₃ : C, 69.00; H, 5.15; N, 4.47; F, 6.06;

Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08%.

Step B: 3-((S)-Azido-(4-fluorolhenyl))acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 liter 3-necked flask, equipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 58.0 ml of 1M potassium bis(trimethylsilyl)amide solution in toluene and 85 ml of THF and was cooled to -78° C. An oven-dried 250 ml round-bottomed flask, equipped with a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 7.20 g (23.0 mmol) of 3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in 40 ml of THF. The acyl oxazolidinone solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the potassium bis(trimethylsilyl)amide solution at such a rate that the internal temperature of the mixture was maintained below -70° C. The acyl oxazolidinone flask was rinsed with 15 ml of THF and the rinse was added, via cannula, to the reaction mixture and the resulting mixture was stirred at -78° C. for 30 minutes. An oven-dried, 250 ml round-bottomed flask, equipped with a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 10.89 g (35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 ml of THF. The azide solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the reaction mixture at such a rate that the internal temperature of the mixture was maintained below -70° C. After 2 minutes, the reaction was quenched with 6.0 ml of glacial acetic acid, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The quenched reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of 50% saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/v hexanes/methylene chloride as the eluant afforded 5.45 g (67%) of the title compound as an oil. ¹ H NMR (400 MHz, CDCl₃) δ 2.86 (1H, dd, J=13.2, 9.6 Hz), 3.40 (1H, dd, J=13.2, 3.2 Hz), 4.09-4.19 (2H, m), 4.62-4.68 (1H, m), 6.14 (1H, s), 7.07-7.47 (9H, m).

Analysis Calcd. for C₁₈ H₁₅ FN₄ O₃ : C, 61.01; H, 4.27; N, 15.81; F, 5.36;

Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34%.

Step C: (S)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (from Step B) in 200 ml of 3:1 v/v THF/water was stirred in an ice bath for 10 minutes. 1,28 g (30.4 mmol) of lithium hydroxide monohydrate was added in one portion and the resulting mixture was stirred cold for 30 minutes. The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was washed with 2×100 ml of methylene chloride and acidified to pH 2 with 2N aqueous hydrochloric acid solution. The resulting mixture was extracted with 2×100 ml of ethyl acetate; the extracts were combined, washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to afford 2.30 g (77%) of the title compound as an oil that was used in the following step without further purification. IR Spectrum (neat, cm⁻¹): 2111, 1724. 1H NMR (400 MHz, CDCl₃) δ 5.06 (1H, s), 7.08-7.45 (4H, m), 8.75 (1H, br s).

Step D: (S)-(4-Fluoronhenyl)glycine

A mixture of 2.30 g (1 1.8 mmol) of (S)-azido-(4-fluorophenyl)acetic acid (from Step C), 250 mg 10% palladium on carbon catalyst and 160 ml 3:1 v/v water/acetic acid was stirred under an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through Celite and the flask and filter cake were rinsed well with ˜1 l of 3:1 v/v water/acetic acid. The filtrate was concentrated in vacuo to about 50 ml of volume. 300 ml of toluene was added and the mixture concentrated to afford a solid. The solid was suspended in 1:1 v/v methanol/ether, filtered and dried to afford 1.99 g (100%) of the title compound. ¹ H NMR (400 MHz, D₂ O+NaOD) δ 3.97 (1H, s), 6.77 (2H, app t, J=8.8 Hz), 7.01 (2H, app t, J=5.6 Hz).

Via Resolution:

Step A' (4-Fluorophenyl)acetyl chloride

A solution of 150 g (0.974 mol) of 4-(fluorophenyl)acetic acid and 1 ml of N,N-dimethylformamide in 500 ml of toluene at 40° C. was treated with 20 ml of thionyl chloride and heated to 40° C. An additional 61.2 ml of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50° C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70° C.

Step B': Methyl 2-bromo-3-(4-fluorophenyl)acetate

A mixture of 150.4 g (0.872 mol) of 4-(fluorophenyl)acetyl chloride (from Step A) and 174.5 g (1.09 mol) of bromine was irradiated at 40-50° C. with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 ml of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuao and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of the title compound, bp=106-110° C.

Step C': Methyl (±)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of methyl ² -bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28 g (0.01 mol) of benzyl triethylammonium chloride in 25 ml of methanol was treated with 6.8 g (0.105 mol) of sodium azide and the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was filtered; the filtrate was diluted with 50 ml of methanol and hydrogenated in the presence of 0.5 g of 10% Pd/C at 50 psi for 1 hour. The solution was filtered and the solvent removed in vacuo. The residue was partitioned between 10% aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution dried over magnesium sulfate and concentrated in vacuo to afford 9.8 g of the title compound as an oil.

Step D': Methyl (S)-(4-fluorophenyl)glycinate

A solution of 58.4 g of methyl (±) 4-(fluorophenyl)glycinate (from Step C') in 110 ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6 g (0.0799 mol) of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6 g, 0.0799 mol) in 110 ml of 7:1 v/v ethanol:water and the resulting solution was allowed to age at room temperature. Ethyl acetate (220 ml) was added after crystallisation was complete and the resulting mixture was cooled to -20° C. and filtered to afford 32.4 g of methyl (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=93.2%). The mother liquors were concentrated in vacuo and the free base was liberated by partitioning between ethyl acetate and aqueous sodium carbonate solution. A solution of free base, so obtained, in 110 ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6 g (0.0799mol) of O,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6 g, 0.0799 mol) in 110 ml of 7:1 v/v ethanol:water and the resulting solution was allowed to age at room temperature. Ethyl acetate (220 ml) was added after crysallisation was complete and the resulting mixture was cooled to -20° C. and filtered to afford 47.0 g of methyl (R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8%). Recycling of the mother liquors and addition of (+)-DBT gave a second crop of 7.4 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=96.4%). The two crops of the (S)-amino ester (39.8 g) were combined in 200 ml of 7:1 v/v ethanol/water, heated for 30 minutes and cooled to room temperature. Addition of ethyl acetate, cooling, and filtration afforded 31.7 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee>98%). Enantiomeric excess was determined by chiral HPLC (Crownpak CR(+) 5% MeOH in aq HClO₄ pH2 1.5 ml/min 40° C. 200nm).

A mixture of 17.5 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt and 32 ml of 5.5N HCl (32 ml) was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 40 ml of water. The aqueous solution was washed (3×30 ml of ethyl acetate) and the layers were separated. The pH of the aqueous layer was adjusted to 7 using ammonium hydroxide and the precipitated solid was filtered to afford 7.4 g of the title compound (ee=98.8%).

DESCRIPTION 2

4-Benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

Step A: N-Benzyl-(S)-(4-fluoronhenyl)glycine

A solution of 1.87 g (1 1.05 mmol) of (S)-(4-fluorophenyl)-glycine (from Description 1) and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1N aqueous sodium hydroxide solution and 11 ml of methanol at 0° C. was treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. Second portions of benzaldehyde (1.12 ml (11.1 mmol)) and sodium borohydride (165 mg (4.4 mmol) were added to the reaction mixture and stirring was continued for 1.5 hours. The reaction mixture was partitioned between 100 ml of ether and 50 ml of water and the layers were separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with 2N aqueous hydrochloric acid solution and the solid that had precipitated was filtered, rinsed well with water, then ether, and dried to afford 1.95 g of the title compound. ¹ H NMR (400 MHz, D₂ O+NaOD) δ 3.33 (2H, AB q, J=8.4 Hz), 3.85 (1H, s), 6.79-7.16 (4H, m).

Step B: 4-Benzyl-3-(S)-(4-fluoroihenyl)-2-morpholinone

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl)glycine, 3.90 ml (22.5 mmol) of N,N-diisopropyl-ethylamine, 6.50 ml (75.0 mmol) of 1,2-dibromoethane and 40 ml of N,N-dimethylformamide was stirred at 100° C. for 20 hours (dissolution of all solids occurred on warming). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 250 ml of ether and 100 ml of 0.5N potassium hydrogen sulfate solution and the layers were separated. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution, 3×150 ml of water, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 125 g of silica gel using 3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the title compound as an oil. ¹ H NMR (400 MHz, CDCl₃) δ 2.65 (1H, dt, J=3.2, 12.8 Hz), 3.00 (1H, dt, J=12.8, 2.8 Hz), 3.16 (1H, d, J=13.6 Hz), 3.76 (1H, d, J=13.6 Hz), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2 Hz), 4.54 (1H, dt, J=2.8, 13.2 Hz), 7.07-7.56 (9H, m).

DESCRIPTION 3

4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of 2.67 g (10.0 mmol) of ⁴ -benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 ml of dry THF was cooled to -78° C. The cold solution was treated with 12.5 ml of 1.0 M L-Selectride® solution in THF, maintaining the internal reaction temperature below -70° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 ml of ether and 50 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid. ¹ H NMR (200 MHz, CDCl₃) δ 2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (1H, app d, J=12.0 Hz), 2.99 (1H, d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6 Hz), 4.00 (1H, d, J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H, d, J=2.6 Hz), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H, s), 8.47 (2H, s).

Analysis Calcd. for C₂₆ H₂₀ F₇ NO₃ : C, 59.21; H, 3.82; N, 2.66; F, 25.21.

Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18%.

DESCRIPTION 4

4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Step A: Dimethyl titanocene

A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml of ether in the dark at 0° C. was treated with 17.5 ml of 1.4M methyllithium solution in ether maintaining the internal temperature below 5° C. The resulting yellow/orange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25 g of ice. The quenched reaction mixture was diluted with 50 ml of ether and 25 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated it vacuo to afford 2.03 g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0° C. for at least 2 weeks without apparent chemical degradation. ¹ H NMR (200 MHz, CDCl₃) δ 0.15 (6H, s), 6.06 (10H, s).

Step B: 4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluoronhenyl)moroholine

A solution of the compound of Description 3 (2.50 g, 4.9 mmol) and 2.50 g (12.0 mmol) of dimethyl titanocene (from Step A) in 35 ml of 11 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71 g (69%) of the title compound as a solid. An analytical sample was obtained via recrystallisation from isopropanol: ¹ H NMR (400 MHz, CDCl₃) δ 2.42 (1H, dt, J=3.6, 12.0 Hz), 2.90 (1H, app d, J=12.0 Hz), 2.91 (1H, d, J=13.6 Hz), 3.62-3.66 (1H, m), 3.72 (1H, d, J=2.6 Hz), 3.94 (1H, d, J=13.6 Hz), 4.09 (1H, dt, J=2.4, 12.0 Hz), 4.75 (1H, d, J=3.2 Hz), 4.82 (1H, d, J=3.2 Hz), 5.32 (1H, d, J=2.6 Hz), 7.09 (2H, t, J=8.8 Hz), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m), 7.80 (1H, s), 7.90 (2H, s).

Analysis Calcd. for C₂₇ H₂₂ F₇ NO₂ : C, 61.72; H, 4.22; N, 2.67; F, 25.31.

Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%.

DESCRIPTION 5

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) morpholine

The compound of Description 4 (4.0 g) was dissolved in ethyl acetate (50 ml) and isopropanol (16 ml). To this solution was added palladium on charcoal (1.5 g) and the mixture was hydrogenated at 40 psi for 36 h. The catalyst was removed by filtration through Celite and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica using 100% ethyl acetate and then 1-10% methanol in ethyl acetate. This afforded isomer A 500 mg (15%) and isomer B 2.6 g (80%) as clear oils--isomer B crystallised on standing. For the title compound: ¹ H NMR (400 MHz, CDCl₃) δ 1.16 (3H, d, J=6.8 Hz), 1.80 (1H, br s), 3.13 (1H, dd, J=3.2, 12.4 Hz), 3.23 (1H, dt, J=3.6, 12.4 Hz), 3.63 (1H, dd, J=2.4, 11,2 Hz), 4.01 (1H, d, J=2.4 Hz), 4.13 (1H, dt, J=3.2, 12.0 Hz), 4.42 (1H, d, J=2.4 Hz), 4.19 (1H, q, J=6.8 Hz), 7.04-7.09 (2H, m), 7.27-7.40 (4H, m), 7.73 (1H, s): MS (FAB) 438 (M+H, 75%), 180 (100%).

HCl salt formation. To a solution of the free base (0.77 g) in diethyl ether (10 ml) was added 1M-HCl in methanol (1.75 ml). The solution was evaporated to dryness and on addition of diethyl ether crystals formed. The solution was filtered and the residue washed with diethyl ether to give the title compound hydrochloride salt. m.p. 248-250° C.

Analysis Calcd. for ₂₀ H₁₈ F₇ NO₂ . HCl: C, 50.70; H, 4.04; N, 2.96; Cl, 7.48;

Found: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31%.

EXAMPLE 1

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1,2,4-triazolo)methylmorpholine

The title compound was prepared in 79% yield from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine (from Description 5) and N-methylcarboxy-2-chloroacetamidrazone using a procedure anaolgous to Example 18 in European Patent Specification No. 0 577 394. ¹ H NMR (CDCl₃ +CD₃ OD, 400 MHz): δ 1.48 (3H, d, J=6.8 Hz), 2.52 (1H, app t, J=10.4 Hz), 2.85-2.88 (2H, m), 3.47 (1H, d, J=2.8 Hz), 3.63 (1H, d, J=4.4 Hz), 3.70 (1H, dd, J=2.0, 11.6 Hz), 4.24 (1H, app t, J=10.8 Hz), 4.35 (1H, d, J=2.8 Hz), 4.91 (1H, q, J=6.8 Hz), 7.07 (2H, app t, J=8.4 Hz), 7.15 (2H, s), 7.37-7.40 (2H, m), 7.65 (1H, s).

Analysis Calcd. for C₂₃ H₂₁ F₇ N₄ O₃ : C, 51.69; H, 3.96; N, 10.48; F, 24.88;

Found: C, 51.74; H, 4.04; N, 10.50; F, 24.59%.

EXAMPLE 2

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl) morpholine

Method A

a) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)-4-propargylmoroholine

Propargyl bromide (1.9 ml) was added to a stirred mixture of the compound of Description 5 (5 g) and potassium carbonate (⁴.76 g) in dry dimethylformamide at 23° C. After 15 min the reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine (1×100 ml) then dried (K₂ CO₃) and concentrated to leave an oil. This was purified by chromatography on silica using ethyl acetate in hexane (1:9 then 1:4) as eluent to afford the title compound as an oil. ¹ H NMR (250 MHz, CDCl₃) δ 1.50 (3H, d, J=6.6 Hz), 2.21 (1H, s), 2.84 (1H, d, J=11.1 Hz), 2.97 (1H, td, J=3.2, 11.7 Hz), 3.26 (2H, d, J=1.8 Hz), 3.62 (1H, d, J=2.2 Hz), 3.71 (1H, dd, J=2.3, 11.1 Hz), 4.33 (2H, m), 4.89 (1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.6 Hz), 7.18 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (CI⁺) m/z 476 (MH, 100%).

b) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylamino-4-oxo-but-2-ynyl)-3-(S)-(4-fluorophenyl)morpholine

A mixture of N,N-dimethylcarbamoyl chloride (0. 195 ml), cuprous iodide (2 mg), bis(triphenylphosphine)palladium (II) chloride (2 mg), triphenylphosphine (3 mg) and the compound described in (a) above (1 g) in triethylamine (4 ml) was heated at 90° C. for 5 h in an inert atmosphere. The mixture was cooled to 23° C. and methanol (1 ml) was added and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water, brine, dried (MgSO₄) and concentrated to leave an oil. The residue was purified by chromatography on silica using ethyl acetate in hexane (1:1) then ethyl acetate as eluant to provide the title compound as an oil. ¹ H NMR (250 MHz, CDCl₃) δ 1.49 (3H, d, J=6.6 Hz), 2.84-3.06 (2H, m), 3.00 (3H, s), 3.17 (3H, s), 3.44 (2H, s), 3.64 (1H, br s), 3.73 (1H, dd, J=2.0, 11.1 Hz), 4.33 (2H, m), 4.88 (1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (CI⁺) m/z 547 (MH, 100%).

c) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-dimethylcarboxamido-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl) morpholine

A mixture of the compound described in (b) above (1.1 g) and sodium azide (0.65 g) in dimethylsulphoxide (7.5 ml) was heated at 70° C. for 17 h. The mixture was cooled to 23° C. and excess dimethylsulphoxide was removed by distillation in vacuo. The residue was partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed with brine (2×20 ml) then dried (MgSO₄) and concentrated to leave an oil. This was purified by chromatography on silica using ethyl acetate in hexane (1:2 then 1:1) and then ethyl acetate as eluent to provide the title compound as a pale yellow foam. ¹ H NMR (360 MHz, CDCl₃) δ 1.47 (3H, d, J=6.6 Hz), 2.64 (1H, m), 2.90 (1H, d, J=11.6 Hz), 3.09 (3H, s), 3.34 (3H, s), 3.65 (3H, m), 3.92 (1H, d, J=15.5 Hz), 4.27 (1H, td, J=2.1, 9.5 Hz), 4.35 (1H, d, J=2.6 Hz), 4.89 (1H, q, J=6.6 Hz), 7.01 (2H, t, J=8.7 Hz), 7.16 (2H, s), 7.39 (2H, br s), 7.64 (1H, s). m/z 590 (MH, 100%).

d) 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl) morpholine

Lithium aluminium hydride (0.47 ml, 1M in tetrahydrofuran) was added dropwise to a solution of the compound described in (c) above (0.11 g) in dry tetrahydrofuran (1 ml) under an inert atmosphere at 23° C. After 30 min sodium hydroxide (10 drops, 1M) was added followed by water (5 drops). Ethyl acetate (50 ml) was then added and the resulting mixture was filtered through a pad of Hyflo™. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica using ethyl acetate in methanol (9:1 then 4:1) as eluant to provide the title compound as a foam. ¹ H NMR (360 MHz, CDCl₃) δ 1.44 (3H, d, J=6.6 Hz), 2.25 (6H, s), 2.57 (1H, td, J=3.4, 8.55 Hz), 2.90 (1H, d, J=11.7 Hz), 3.25 (1H, d, J=14.0 Hz), 3.43 (1H, d, J=13.6 Hz), 3.45 (1H, d, J=2.2 Hz), 3.53 (1H, d, J=13.6 Hz), 3.61 (1H, d, J=11,2 Hz), 3.78 (1H, d, J=14.0 Hz), 4.22 (1H, t, J=9.3 Hz), 4.32 (1H, d, J=2.2 Hz), 4.86 (1H, q, J=6.6 Hz), 7.06 (2H, t, J=8.7 Hz), 7.16 (21-1, s), 7.48 (2H, br s), 7.63 (1H, s). m/z 576 (MH).

Method B

a) 2-(R)-1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut-2-ynyl)morpholine

A solution of the product of Description 5 (free base, 5 g) in N,N-dimethylformamide (20 ml) was slowly added to a heated (50° C.) solution of 1,4-dichlorbut-2-yne (2.2 ml) and potassium carbonate (4.8 g) in N,N-dimethylformamide (20 ml). The solution was heated for a further 5 h at 50° C. and then the solvent removed in vacuo. To the residue was added water (400 ml) and the product extracted into ethyl acetate (3×150 ml). The combined organic phase washed with water, saturated brine and dried (MgSO₄). The solvent was removed in vacuo and the residue chromatographed on silica gel (eluting with 10% ethyl acetate in petroleum ether bp 60-80° C.) to give the title compound. ¹ H NMR (250 MHz, CDCl₃) δ 1.41 (3H, d, J=6.6 Hz), 2.80 (1H, app. t, J=10.8 Hz), 2.87 (1H, td, J=3.5 Hz, 11.7 Hz), 3.22 (2H, t, J=1.9 Hz), 3.52 (1H, d, J=2.8 Hz), 3.68 (1H, d, J=1.4 Hz, 11.1 Hz), 4.00 (2H, t, J=1.9 Hz), 4.22-4.32 (2H, m), 4.81 (1H, q, J=6.6 Hz), 6.96 (2H, t, J=8.7 Hz), 7.10 (2H, s), 7.31 (2H, br s), 7.56 (1H, s). m/z (CI⁺) 524 (M+H, 100%).

b) N-(4-Azidobut-2-ynyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)morpholine

To a solution of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut-2-ynyl)morpholine (4 g) in dimethyl sulphoxide (17 ml) was added sodium azide (0.562 g). The solution was stirred for 20 h and aqueous ammonium chloride and ethyl acetate were added. The organic phase was washed with water (2 times), saturated brine and dried (MgSO₄). The solvent was removed in vacuo and the residue chromatographed on silica gel (eluting with 20% ethyl acetate in petroleum ether bp 60-80° C.) to give the title compound. ¹ H NMR (360 MHz, CDCl₃) δ 1.48 (3H, s, J=6.6 Hz), 2.87 (1H, app t, J=10.2 Hz), 2.98 (1H, td, J=3.6, 11.7 Hz), 3.35 (2H, t, J=1.9 Hz), 3.61 (1H, d, J=2.8 Hz), 3.72 (1H, dq, J=1.4 Hz, 10.0 Hz), 3.92 (2H, t, J=1.9 Hz), 4.30-4.40 (2H, m), 4.89(1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.27 (2H, br s), 7.63 (1H, s).

c) 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl) morpholine

Dimethylamine (approximately 10 ml) was condensed at -80° C. in a pressure tube and to this was added a solution of N-(4-azidobut-2-ynyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl) morpholine (3.2 g) in dioxan (15 ml). The tube was sealed and the solution was heated at 90° C. for 16 h. The solution was evaporated to dryness and the residue chromatographed on silica gel (eluting with 5% methanol in dichloromethane containing 0.25% ammonia (SG. 0.88)) and the fractions containing the desired product were evaporated in vacuo to give the title compound. To a solution of this residue in diethyl ether was added 1M HCl in methanol. The solution was evaporated to dryness and redissolved in diethyl ether to give crystals of the title compound hydrochloride salt. m.p. 194-198° C., [α]²² _(D) +65.00 (c=0.5, H₂ O).

EXAMPLE 3

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(pyrrolidinomethyl)-1,2,3-triazol-4-yl) methylmorpholine

The title compound was prepared from the product of Description 5 by a method analogous to that described in Example 2 (Method B). m/z (CI⁺) 602 (M+H).

Analysis Calcd. for C₂₈ H₃₀ F-N₅ O₂ : C, 55.90; H, 5.03; N, 11.64;

Found: C, 55.71; H, 4.86; N, 11.53%.

EXAMPLE 4

4-(5-Azetidinylmethyl-1,2 3-triazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)morpholine

This compound was prepared following the method described in Example 2 (Method B) using the compound from Description 5 as starting material. 1H NMR (360 MHz, CDCl₃) δ 1.44 (3H, d, J=6.6 Hz), 2.14 (2H, m), 2.55 (1H, dd, J=3.4, 11.9 Hz), 2.87 (1H, d, J=11.9 Hz), 3.21-3.44 (6H, m), 3.58-3.67 (3H, m), 3.75 (1H, d, J=14.0 Hz), 4.2 (1H, t, J=9.3 Hz), 4.31 (1H, d, J=2.8 Hz), 4.85 (1H, m), .06 (2H, t, J=8.7 Hz), 7.16 (1H, s), 7.47 (2H, br s), 7.63 (1H, s).

EXAMPLE 5

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4(?)-monophosphoryl-5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, dipotassium salt

A solution of 450 mg (0.84 mmol) of 2-(R)-(1-(R)-(3,5 -bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine (Example 1) in 20 ml of THF at 0° C. was treated with 0.84 ml of 1.0 M n-butyllithium solution in hexanes. The resulting solution was stirred cold for 5 minutes and was treated with 630 mg (1.17 mmol) of tetrabenzylpyrophosphate in one portion as a solid. The cooling bath was removed and the reaction was stirred at room temperature for 45 minutes. The reaction was quenched with 25 ml of saturated aqueous sodium bicarbonate solution and was extracted with 50 ml of ethyl ether. The organic layer was separated, washed with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of 0.5N aqueous potassium hydrogen sulfate solution, 25 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude dibenzyl ester was dissolved in 25 ml of methanol. A solution of 168 mg (1.68 mmol) of potassium bicarbonate was added to the ester solution and the resulting mixture was hydrogenated at 40 psi in the presence of 45 mg of 10% palladium on carbon catalyst for 75 minutes. The catalyst was filtered onto a pad of Celite™; the reaction flask and filter cake were rinsed well with methanol (˜200 ml), the filtrate was concentrated in vacuo and dried. The residue was partially dissolved in methanol and filtered; the filtrate was concentrated and dried. The resulting solid was recrystallized from isopropanol to afford 280 mg of crude title compound. The solid was partitioned between 40 ml of ethyl ether and 20 ml of water; mixing of the layers resulted in an emulsion. Centrifugation at 2800 rpm for 15 minutes broke the emulsion; the aqueous layer was separated and lyophilized to afford 188 mg (33%) of the compound tentatively identified as 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2.4-triazolo)methyl)morpholine, dipotassium salt as a solid. ¹ H NMR (CD₃ OD, 500 MHz): δ 1.43 (3H, d, J=6.5 Hz), 2.45 (1H, app t, J=8.5 Hz), 2.80 (1H, d, J=14.0 Hz), 2.92 (1H, d, J=11.5 Hz), 3.47-3.66 (4H, m), 4.25 (1H, app t, J=11.5 Hz), 4.36 (1H, d, J=1.5 Hz), 4.94 (1H, q, J=6.6 Hz), 7.05 (2H, t, J=8.5 Hz), 7.31(2H, s), 7.52 (2H, br s), 7.71 (1H, s). ¹³ C NMR (CD₃ OD, 125 MHz): δ 24.7, 52.3, 53.4, 60.5, 70.6, 73.7, 97.2, 116.1 (d, J=21.9), 122.3, 124.6 (q, J=271.0), 127.7, 132,3, 132.6, 132.8, 134.3, 145.2 (d, J=11.0), 147.5, 159.0 (d, J=10.1), 164.0 (d, J=244.4).

The efficacy of a combination of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine in the prevention of motion sickness can be demonstrated, for example, using a device which elicits motion sickness in cats, as described by J. B. Lucot, Mechanisms and Control of Emesis, A. L. Bianchi et al (Eds.) Colloques INSERM, John Libbey Eurotext, (1992) 223, 195-201).

Briefly, a motorised motion testing device modelled after a Ferris wheel is used to produce motion sickness. Cats ride alone in two clear plastic boxes suspended from the ends of a 0.89 meter beam that rotates about a horizontal axis. The boxes are counterrotated by a chain and sprocket system such that the boxes remain vertical. The most provocative motion is achieved at a rotation rate of 0.28 Hz (17rpm). A standard test is defined as 30min. of motion at 0.28 Hz followed by 1 min. of observation at rest. Cats are screened for susceptability to motion sickness in this model, and studies have shown that, when tested at two week intervals, no habituation to the motion sickness occurs.

Alternatively, the efficacy of a combination of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine in the prevention of motion sickness may be demonstrated using cross-coupled stimulation which elicits motion sickness in man, as described by J. R. R. Stott et al., Br. J. Clin. Pharmac., (1989) 27, 147-157.

Briefly, healthy volunteers are seated on a rotated chair surrounded by an enclosure that rotates with the chair thus obscuring a view of the room. Rotation of the chair is started at 3°s⁻¹ and incremented by 3°s⁻¹ every minute up to a maximum of 90°s⁻¹, and maintained at this speed for a further 10 min. During chair rotation the subject makes 60° head movements to the left and right in roll and forward and back in pitch. The forward movement also involves forward flexion of the trunk to bring the forehead into contact with a pad situated at arms length in front of the subject. This series of head movements during yaw axis rotation (cross-coupled stimulation) leads to motion sickness in most subjects. Every 30 seconds the subject reports their overall level of malaise using a scale of 1 to 10 (1 being a feeling of complete well being; 10 being a wish to stop the test). The test is discontinued after 40 min. or, more usually, when the subject reaches a malaise score of 10.

A combination of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine is administered to the subject up to 2 hours prior to commencement of the cross-coupled stimulation.

The following examples illustrate pharmaceutical compositions according to the invention.

These formulations may be prepared with separate active ingredients or with with a combination of active ingredients in one composition. In such combined preparations, the ratio of tachykinin antagonist to muscarinic antagonist and/or antihistamine will depend upon the choice of active ingredients.

EXAMPLE 6A

Tablets containing 1-25 mg of compound

    ______________________________________                                                       Amount mg                                                        ______________________________________                                         Active Ingredients(s)                                                                          1.0        2.0    25.0                                           Microcrystalline cellulose 20.0 20.0 20.0                                      Modified food corn starch 20.0 20.0 20.0                                       Lactose 58.5 57.5 34.5                                                         Magnesium Stearate 0.5 0.5 0.5                                               ______________________________________                                    

EXAMPLE 6B

Tablets containing 26-100 mg of compound

    ______________________________________                                                       Amount mg                                                        ______________________________________                                         Active Ingredients(s)                                                                          26.0       50.0   100.0                                          Microcrystalline cellulose 80.0 80.0 80.0                                      Modified food corn starch 80.0 80.0 80.0                                       Lactose 213.5 189.5 139.5                                                      Magnesium Stearate 0.5 0.5 0.5                                               ______________________________________                                    

The active ingredient(s) cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 7

Parenteral injection

    ______________________________________                                                             Amount                                                     ______________________________________                                         Active Ingredient(s)  1 to 100                                                                               mg                                                 Citric Acid Monohydrate 0.75 mg                                                Sodium Phosphate 4.5 mg                                                        Sodium Chloride 9 mg                                                           Water for injection to 10 ml                                                 ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient(s) is (are) dissolved or suspended in the solution and made up to volume.

EXAMPLE 8

Topical formulation

    ______________________________________                                                             Amount                                                     ______________________________________                                         Active Ingredient(s)  1-10    g                                                  Emulsifying Wax 30 g                                                           Liquid paraffin 20 g                                                           White Soft Paraffin to 100 g                                                 ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient(s) is (are) is added and stirring continued until dispersed. The mixture is then cooled until solid.

EXAMPLE 9A

(Surface-Active Agent) Injection Formulation

    ______________________________________                                         Active Ingredient(s)   up to 10 mg/kg                                            Tween 80 ™  up to 2.5%                                                      [in 5% aqueous mannitol (isotonic)]                                          ______________________________________                                    

The active ingredient(s) is (are) dissolved directly in a solution of the commercially available Tween 80™ (polyoxyethylenesorbitan monooleate) and 5% aqueous mannitol (isotonic).

EXAMPLE 9B

(Emulsion) Injection Formulation

    ______________________________________                                         Active Ingredient(s)   up to 30 mg/ml                                            Intralipid ™ (10-20%)                                                     ______________________________________                                    

The active ingredient(s) is (are) dissolved directly in the commercially available Intralipid™ (10 or 20%) to form an emulsion.

EXAMPLE 9C

Alternative (Emulsion) Injectable Formulation

    ______________________________________                                                             Amount                                                     ______________________________________                                         Active Ingredient(s)  0.1-10  mg                                                 Soybean oil 100 mg                                                             Egg Phospholipid 6 mg                                                          Glycerol 22 mg                                                                 Water for injection to 1 ml                                                  ______________________________________                                    

All materials are sterilized and pyrogen free. The active ingredient(s) is (are) dissolved in soybean oil. An emulsion is then formed by mixing this solution with the egg phospholipid, glycerol and water. The emulsion is then sealed in sterile vials. 

What is claimed is:
 1. A method for the treatment or prevention of motion sickness in a patient which comprises administering to the patient an amount of a tachykinin antagonist and an amount of a muscarinic antagonist and/or an antihistamine, such that they give effective relief from motion sickness and such that the amount of the muscarinic antagonist and/or the antihistamine is less than would otherwise be required in the absence of the tachykinin antagoinst.
 2. The method of claim I wherein the tachykinin antagonist is a compound of formula (I): ##STR29## or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁₋₆ alkyl which is substituted with one or more of the substituents selected from:heterocycle, wherein the heterocycle is selected from the group consisting of:(A) benzimidazolyl, (B) imidazolyl, (C) indolyl, (D) pyrazolyl, (E) pyrrolyl, (F) tetrazolyl, (G) triazolyl, (H) pyrrolidinyl,and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: (i) C₁₋₆ alkyl, unsubstituted or substituted with halo, --CF₃, --OCH₃, or phenyl, (ii) C₁₋₆ alkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) halo, (vii) cyano, (viii) phenyl, (ix) trifluoromethyl, (x) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m is 0, 1 or 2, wherein R⁹ and R¹⁰ are independently selected from:(I) hydrogen, (II) C₁₋₆ alkyl, (III) hydroxy-C₁₋₆ alkyl, and (IV) phenyl, (xi) --SR⁹, (xii) --NR⁹ COR¹⁰, (xiii) --CONR⁹ R¹⁰, (xiv) --CO₂ R⁹, and (xv) --(CH₂)_(m) --OR⁹ ; R² and R³ are independently selected from the group consisting of:(1) hydrogen, (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --NR⁹ R¹⁰, (i) --NR⁹ COR¹⁰, (j) --NR⁹ CO₂ R¹⁰, (k) --CONR⁹ R¹⁰, (l) --COR⁹, and (m) --CO₂ R⁹ ; (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --CONR⁹ R¹⁰, (i) --COR⁹, and (j) --CO₂ R⁹ ; (4) C₂₋₆ alkynyl; (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) C 16alkoxy, (c) C₁₋₆ alkyl, (d) C₂₋₅ alkenyl, (e) halo, (f) --CN, (g) --NO₂, (h) --CF₃, (i) --(CH₂)_(m) --NR⁹ R¹⁰, (j) --NR⁹ COR¹⁰, (k) --NR⁹ CO₂ R¹⁰, (l) --CONR⁹ R¹⁰, (m) --CO₂ NR⁹ R¹⁰, (n) --COR⁹, and (o) --CO₂ R⁹ ; X is --O--; R⁴ is selected from the group consisting of: ##STR30## (2) --Y--C₁₋₈ alkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --NR⁹ R¹⁰, (i) --NR⁹ COR¹⁰, (j) --NR⁹ CO₂ R¹⁰, (k) --CONR⁹ R¹⁰, (l) --COR⁹, (m) --CO₂ R⁹ ; (3) --Y--C₂₋₆ alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --CONR⁹ R¹⁰, (i) --COR⁹, (j) --CO₂ R⁹, (4) --O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R⁶, R⁷ and R⁸ ; R⁵ is selected from the group consisting of:(1) phenyl, unsubstituted or substituted with one or more of R¹¹, R¹² and R¹³ (2) C₁₋₈ alkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --NR⁹ R¹⁰, (i) --NR⁹ COR¹⁰, (j) --NR⁹ CO₂ R¹⁰, (k) --CONR⁹ R¹⁰, (l) --COR⁹, (m) --CO₂ R⁹ ; (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --CONR⁹ R¹⁰, (i) --COR⁹, (j) --CO₂ R⁹ ; R⁶, R⁷ and RS are independently selected from the group consisting of:(1) hydrogen; (2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --NR⁹ R¹⁰, (i) --NR⁹ COR¹⁰, (j) --NR⁹ CO₂ R¹⁰, (k) --CONR⁹ R¹⁰, (l) --COR⁹, and (m) --CO₂ R⁹ ; (3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo, (h) --CONR⁹ R¹⁰, (i) --COR⁹, (j) --CO₂ R⁹ ; (4) C₂₋₆ alkynyl; (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy, (b) C₁₋₆ alkoxy, (c) C₁₋₆ alkyl, (d) C₂₋₅ alkenyl, (e) halo, (f) --CN, (g) --NO₂, (h) --CF₃, (i) --(CH₂)_(m) --NR⁹ R¹⁰, (j) --NR⁹ COR¹⁰, (k) --NR⁹ CO₂ R¹⁰, (l) --CONR⁹ R¹⁰, (m) --CO₂ NR⁹ R¹⁰, (n) --COR⁹, (o) --CO₂ R⁹ ; (6) halo, (7) --CN, (8) --CF₃, (9) --NO₂, (10) --SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅ alkyl, (11) --SOR¹⁴, (12) --SO₂ R¹⁴, (13) NR⁹ COR¹⁰, (14) CONR⁹ COR¹⁰, (15) NR⁹ R¹⁰, (16) NR⁹ CO₂ R¹⁰, (17) hydroxy, (18) C₁₋₆ alkoxy, (19) COR⁹, and (20) CO₂ R⁹ ; R¹¹, R¹² and R¹³ are independently selected from the definitions of R⁶, R⁷ and R⁸ ; Y is selected from the group consisting of:(1) a single bond, (2) --O--, (3) --S--, (4) --CO--, (5) --CH₂ --, (6) --CHR¹⁵ --, and (7) --CR¹⁵ R ⁶ --, wherein R¹⁵ and R¹⁶ are independently selected from the group consisting of:(a) C₁₋₆ alkyl, unsubstituted or substituted with one or more of the substituents selected from: (i) hydroxy, (ii) oxo, (iii) C₁₋₆ alkoxy, (iv) phenyl-C₁₋₃ alkoxy, (v) phenyl, (vi) --CN, (vii) halo, (viii) --NR⁹ R¹⁰, (ix) --NR⁹ COR¹⁰, (x) --NR⁹ CO₂ R¹⁰, (xi) --CONR⁹ R¹⁰, (xii) --COR⁹, and (xiii) --CO₂ R⁹ ; (b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (i) hydroxy, (ii) C₁₋₆ alkoxy, (iii) C₁₋₆ alkyl, (iv) C₂₋₅ alkenyl, (v) halo, (vi) --CN, (vii) --NO₂, (viii) --CF₃, (ix) --(CH₂)_(m) --NR⁹ R¹⁰, (x) --NR⁹ COR¹⁰, (xi) --NR⁹ CO₂ R¹⁰, (xii) --CONR⁹ R¹⁰, (xiii) --CO₂ NR⁹ R¹⁰, (xiv) --COR⁹, and (xv) --CO₂ R⁹ ; Z is selected from:(1) hydrogen, (2) C₁₋₄ alkyl, and (3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR¹⁵ --, then Z and R¹⁵ may be joined together to form a double bond.
 3. The method of claim 1 wherein the muscarinic antagonist is scopolamine, or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1 wherein the antihistamine is selected from buclizine, chlorcyclizine, cinnarizine, cyclizine, dimenhydrinate, diphenhydramine, flunarizine, meclozine, pheniramine, promethazine and propiomazine; or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1 wherein the muscarinic antagonist and/or antihistamine is selected from promethazine, chlorpromethazine, methotimeprazine, perphenazine, prochlorperazine and trifluoperazine; or a pharmaceutically acceptable salt thereof.
 6. A pharmaceutical composition comprising a tachykinin antagonist and a muscarinic antagonist and/or antihistamine, together with at least one pharmaceutically acceptable carrier or excipient. 